Biomedical subjects

V E Baracos

Publications and source records attributed to V E Baracos.

At least 37 records · Page 2Linked to original sources

PubMed1999

Jejunal mucosal protein synthesis: validation of luminal flooding dose method and effect of luminal osmolarity.

To validate a system to study acute regulation of protein synthesis in intestinal mucosa by luminal nutrients, we compared the fractional rate of protein synthesis (Ks) in jejunal mucosa using the intravenous flooding dose technique with the administration of a comparable concentration and specific activity of tracer in a luminal perfusate. Routes of tracer administration and surgery and perfusion trauma had no effect on mucosal Ks. Furthermore, four 10-cm jejunal segments (within a piglet) simultaneously but separately perfused with a luminal flooding dose had similar Ks values (mean, 43 +/- 2%/day; P > 0.05). Nutrient solutions perfused through four intestinal segments within an animal did not affect plasma levels of most amino acids or glucose. Because cellular hydration is important in regulating metabolism, the effects of physiological variation in luminal osmolarity were studied. Luminal osmolarities between 250 and 380 mosM did not affect mucosal Ks. The system described allows multiple comparisons within an animal and provides a robust model to study acute modulation of protein synthesis in intestinal mucosa by luminal stimuli.

Amino Acids↗

PubMed1999

Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets.

Dietary supplementation with glutamine (Gln), arginine (Arg) or ornithine 2-oxoglutarate (alpha-ketoglutarate; OKG) has attracted recent attention for the potential to improve anti-cancer immune function. However, since these compounds have not been compared systematically in an internally controlled study, their relative efficacy is difficult to estimate. Buffalo rats were fed on nutritionally complete semi-purified diets supplemented with Gln, Arg or OKG for 14 days after implantation of the Morris hepatoma 7777 (n>/=7 per diet). The control diet was made isonitrogenous and isoenergetic by addition of a mixture of non-essential amino acids. After 14 days, peritoneal macrophages and splenocytes were isolated to determine cell phenotypes, macrophage cytostatic activity and natural killer (NK) cell cytotoxicity, as well as nitric oxide (NO) and cytokine production. Diet had no effect on tumour weight (1.6+/-0.2 g; n=59). However, rats fed OKG had increased macrophage cytostatic activity and NK cell cytotoxicity (P<0.05). Although enhanced killing ability by NK cells was associated with higher splenocyte NO production (P<0.04), increased cytotoxicity was not inhibited by a specific inhibitor of inducible NO synthase. The proportion of interleukin-2-receptor-positive T cells after stimulation increased in rats fed OKG (P<0.05); however, cytokine production was not affected by diet. None of OKG, Gln or Arg altered tumour growth compared with a control mixture of non-essential amino acids. These results suggest no net advantage for anti-cancer immunity, but do not preclude benefits in immune responses to disease recurrence or metastasis, therapy or secondary infection.

Analysis of Variance↗

PubMed1998

Anabolic and catabolic mediators.

Negative N balance, and skeletal muscle wasting are associated with many disease states. Depletion of skeletal muscle mass is recognized as critical to overall survival of the patient and can prolong rehabilitation to normal physiological function following recovery. The biochemical mechanisms of muscle wasting have been most fully investigated in animal models. These studies indicate a role for suppressed protein synthesis as well as activated proteolysis, and therefore to a need for both anabolic as well as anti-catabolic therapies. Multiple humoral factors are implicated in altered muscle protein metabolism, however the identity of all of the factors involved and their interrelationships are less well characterized. The role of specific mediators in different clinical instances of muscle protein loss is relatively poorly understood, and successful treatment will depend on the ability to identify the different catabolic phenotypes in patients.

Animals↗

PubMed1998

Feeding lactating primiparous sows to establish three divergent metabolic states: II. Effect on nitrogen partitioning and skeletal muscle composition.

We established an experimental model to study nitrogen (N) partitioning in lactating primiparous sows alimented to three levels of nutrient intake. Thirty-six sows fitted with a gastric cannula and fed a 15.4 MJ DE/kg and 18.6% CP diet were allocated to one of three treatments after farrowing: 1) ad libitum-fed; 2) restricted-fed to 55% of the ad libitum feed intake; and 3) superalimented to at least 125% of the ad libitum feed intake. These feed intakes were successfully achieved throughout lactation. Nitrogen balance was studied for three 5-d periods starting on d 2, 11, and 19 of lactation, and a triceps muscle biopsy was taken on d 26. For all treatments, N intake increased, milk N production increased, urinary N losses decreased, but fecal N losses increased as the 28-d lactation progressed. Restricted-fed sows had the lowest fecal N and urinary losses and mobilized the most maternal protein (-23.0 vs -7.4 +/- 6.5 g N/d for ad libitum-fed sows) during lactation. As a consequence of these economies, and extensive protein mobilization, restricted-fed sows were able to maintain milk N production similar to that of sows on the other treatments. Superalimented sows did not mobilize protein, had the poorest protein digestibility, directed the least digestible N toward milk (40.1 vs 78.3% in restricted-fed sows), and produced amounts of milk N similar to those produced by sows on the other treatments. The treatment differences in N retention measured by N balance were reflected in differences in skeletal muscle variables and urinary creatinine. Skeletal muscle cell size (protein:DNA ratio) and protein synthetic capacity (RNA:DNA ratio) increased in response to feed intake. The protein:DNA ratio increased (P < .01) linearly and the RNA:DNA ratio increased (P < .05) in a curvilinear manner. These data suggest that primiparous sows partition additional retained N toward their maternal reserves rather than milk N. They also suggest that sows fed inadequate N intakes maintain milk production by mobilizing maternal protein reserves. Such sows also conserve maternal N during lactation, possibly by reducing muscle protein synthesis.

Amino Acids↗

PubMed1997

Dietary L-glutamine supplementation reduces the growth of the Morris Hepatoma 7777 in exercise-trained and sedentary rats.

Dietary glutamine supplementation and exercise have been reported independently to enhance immune function and reduce tumor growth. We study the effect of both of these interventions on the growth of the Morris Hepatoma 7777, implanted in 59 female Sprague-Dawley Buffalo rats. Rats were fed a nutritionally complete, purified diet with or without L-glutamine 20 g/kg diet and randomized to swim 3 h/d or to remain sedentary. After 14 d, the mean tumor weight of glutamine-supplemented rats was lower (P < 0.0001) than that of unsupplemented rats (5.8 +/- 0.4 vs. 8.7 +/- 0.5 g, respectively). Exercise did not alter tumor growth. Glutamine supplementation increased [3H] thymidine incorporation by splenocytes incubated with Concanavalin A and the proportion of natural killer cells in spleen, but not cytotoxic activity against YAC-1 cells. Glutamine supplementation did not alter glutamine concentrations in plasma (691 +/- 12 mumol/L) or soleus muscle (5328 +/- 102 pmol/mg) but resulted in higher (P < 0.004) plasma concentrations of leucine, isoleucine and valine, precursors of glutamine. Splenocytes from exercised rats had a higher (P < 0.001) mitogen response than those from sedentary rats. Isolated tumor cells demonstrated high rates of non-oxidative glucose and glutamine metabolism and consumption of glutamine, tryptophan and methionine. However, neither diet nor exercise significantly affected glucose or glutamine metabolism by tumor cells. The precise mechanism of tumor growth suppression by oral glutamine supplementation is not clear but may be related to changes in substrate availability, improved tumor-directed natural killer cytotoxic activity or a faster response to an immune challenge.

Amino Acids↗

PubMed1997

Dietary L-glutamine does not improve lymphocyte metabolism or function in exercise-trained rats.

Decreased glutamine availability is proposed as a mechanism for changes in immune function with intense exhaustive exercise. Less is known about the immunomodulatory effects of regular nonexhaustive exercise. To determine the effects of low intensity regular exercise and dietary glutamine supplementation on plasma glutamine concentrations, lymphocyte metabolism, and immune function, male (278 +/- 5 g) and female (182 +/- 1 g) Sprague-Dawley Buffalo rats were fed nutritionally complete casein-based semi-purified diets +/- 2% w/w glutamine. Rats were trained (21 d), as confirmed by higher (P < 0.05) succinate dehydrogenase activity in soleus muscle, to swim 2 or 4 h.d-1 or remained sedentary. Exercise lowered plasma concentrations of tryptophan, glutamate, methionine, alanine, threonine, aspartate, asparagine, and ornithine and increased the lysine concentration (P < 0.05). Neither diet nor exercise altered plasma glutamine concentrations, lymphocyte phenotypes in spleen, or the in vitro rates of splenocyte energy metabolism (production of glucose and glutamine metabolites or ATP concentrations in the incubation media). Compared with nonsupplemented rats, splenic cytolytic activity (lysis of 51Cr labeled YAC-1 cells) was reduced (P < 0.05) in the glutamine-supplemented exercising group. Under these conditions, glutamine supplementation does not appear to provide any added benefit to the exercise-trained animal.

Amino Acids↗

PubMed1996

Protein metabolism in cachectic tumor-bearing rats: effect of tumor excision.

The effect of tumor resection on protein metabolism in cancer-bearing subjects is poorly documented. We explored changes in nitrogen (N) and protein metabolism after excision of tumors both at the whole body level (N balance) and at the tissue level, including skeletal muscle, small intestine, and liver. Sixteen male Sprague-Dawley rats (approximately 375 g) bearing subcutaneous Morris hepatoma 7777 for 6 weeks were either operated for tumor excision and studied for 10 days postoperatively (n = 10) or sacrificed on the day of surgery as tumor-bearing controls; operated and unoperated tumor-bearing rats were compared with healthy rats (n = 16). Tumors, which grew to a mass of 74 +/- 7 g (mean +/- SEM), induced significant loss of body mass (-27 +/- 13 g) and protein depletion in epitrochlearis muscle (EPI) (-38%) and small intestine (-42%) vs healthy rats. Tumor significantly decreased muscle protein synthesis vs healthy rats (7.14 +/- 0.5 vs 10.7 +/- 0.5 nmol phenylalanine (Phe)/EPI/3 hr), net degradation (21.7 +/- 2.9 vs 30.6 +/- 2.5 nmol Phe/EPI/3 hr) and degradation (28.8 +/- 2.7 vs 41.4 +/- 2.5 nmol Phe/EPI/3 hr). In 50% of operated rats, tumor removal was followed immediately by increased food intake, body weight, and N balance; in other rats, this was delayed by 2-4 days. By 6 days postoperative, all rats were gaining weight and had normal food intake; wasting was abolished in small intestine, but not in skeletal muscle (protein mass -43% vs healthy rats, P < 0.05). Postoperative rats maintained lower muscle protein degradation (28.2 +/- 2.0 vs 41.4 +/- 2.5 nmol Phe/EPI/3 hr, P < 0.05) than healthy rats; protein synthesis was no longer reduced. In skeletal muscle, protein synthesis and protein deposition were related to levels of postoperative food intake (r = 0.91 and 0.98, respectively; P < 0.05). Following tumor excision, reversal of cancer cachexia appeared to be highly dependent on the level of postoperative food intake.

Animals↗

PubMed1996

Reduced splenocyte metabolism and immune function in rats implanted with the Morris Hepatoma 7777.

Although the immune system is important in antitumor defense, little is know about the immune response during progressive tumor growth. Sprague-Dawley rats (171 +/- 3g) of the Buffalo strain were implanted with the Morris Hepatoma 7777 ([MH 7777] a poorly differentiated, rapidly growing tumor) and killed either 2 (T2) or 3 (T3) weeks postimplantation when the tumor weighed 3.0 +/- 0.4 and 14 +/- 1 g, respectively. Splenocytes were isolated and their phenotypes, metabolism (metabolite production from glucose and glutamine), proliferative response ([3H]thymidine incorporation in response to polyclonal mitogens), and natural killer (NK) cytotoxicity (lysis of YAC-1 cells) were determined. Five rats were killed with the T2 group to serve as non-tumor-bearing controls (T0). Food intake and nontumor body weight decreased (P < .01) 14 days after tumor implantation. There was a progressive decrease (T3 < T2 < T0) in splenic mitogen responses (P < .05) and plasma essential and nonessential amino acid concentrations (P < .05). Compared with T0, NK cytotoxic activity was significantly (P < .05) lower at T2 and higher at T3. The presence of the tumor at both T2 and T3 resulted in lower production of metabolites from glucose and glutamine by splenocytes. The proportion of CD8+ cells was lower (P < .05) and the proportion of B cells and macrophages higher (P < .05) in spleens from tumor-bearing rats. In conclusion, the presence of even a small tumor burden (1.4% of body weight) significantly altered the host's immune function and metabolism. A larger tumor burden (6% of body weight) increased NK cytotoxic activity and further reduced cell-mediated immune function.

Amino Acids↗

PubMed1996

Dietary fat modifies exercise-dependent glucose transport in skeletal muscle.

Exercise stimulates muscle glucose uptake both directly and by increasing the sensitivity of this process to insulin. This study was designed to investigate whether the level of dietary fat would interact with the action of acute exercise in the presence or absence of insulin. Weanling female Sprague-Dawley rats were fed two levels of dietary fat (5 vs. 20%; wt/wt) for 6 wk. Rats then remained sedentary or were exercised by a single bout of swimming for a total of 2 h with 5-min rest intervals each 0.5 h. Basal (insulin-independent) and insulin-stimulated glucose uptake rates were determined in isolated epitrochlearis muscles by using 3-O-[methyl-3H]methyl-D-glucose. Muscles of sedentary rats fed a high-fat diet showed decreased glucose uptake overall because of a marked decrease in insulin-stimulated uptake. Muscles of rats fed a high-fat diet also showed considerable impairment of insulin-dependent glucose uptake measured both immediately and 3.5 h after exercise. Glucose uptake was suppressed by 64% at half-maximal concentrations of insulin (0.8 nM) and by 34% at maximally stimulating (20 nM) insulin levels. This lowered sensitivity and response to insulin were not altered by acute exercise. Glucose uptake in response to acute exercise (insulin independent) was quantitatively similar in rats fed high- and low-fat diets; rats on high-fat diet, however, showed higher insulin-independent glucose uptake at 3.5 h after exercise.

Animals↗

PubMed1996

Effects of ranolazine on oxidative substrate preference in epitrochlearis muscle.

Ranolazine is an novel investigational antianginal agent that stimulates glucose oxidation in isolated rat hearts. This study determined its effects on metabolic substrate and O2 utilization in an in vitro skeletal muscle preparation, the rat epitrochlearis muscle. Muscles were superfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 5.5 mM glucose, 0.5 mM lactate, and a physiological amino acid mixture. Perfusate also contained either 1) [U-14C]glucose for measurement of glucose oxidation or 2) [9,10-3H]palmitate and [U-14C]lactate for measurement of palmitate and lactate oxidation. Addition of ranolazine (10 microM) significantly stimulated glucose oxidation and decreased palmitate oxidation but had no effect on lactate oxidation. Overall, the calculated relative contribution of glucose oxidation to aerobic ATP production increased from 12 to 33%, whereas from palmitate it decreased from 55 to 26%. Ranolazine did not alter tissue malonyl-CoA contents, making it unlikely that the decrease in palmitate oxidation caused by ranolazine is due to a decrease in the activity of acetyl-CoA carboxylase. These data demonstrate that ranolazine can shift energy substrate preference in skeletal muscle, which could potentially prove useful in ischemic disorders of skeletal muscle.

Acetanilides↗

PubMed1995

Negative impact of cancer chemotherapy on protein metabolism in healthy and tumor-bearing rats.

Although chemotherapeutic agents are widely used in the treatment of cancer, few experimental data are available on their effects on host N metabolism. We studied the effects of a single intraperitoneal (IP) injection of cyclophosphamide ([CYP] 120 mg/kg), 5-fluorouracil ([5-FU], 50 mg/kg), cisplatinum ([CDDP], 5 mg/kg), or methotrexate ([MTX], 30 mg/kg). N balance was studied for 6 days following chemotherapy in healthy rats (n = 40) and in rats bearing Morris Hepatoma 7777 ([MH7777] n = 40) in a situation comparable to that of human cancer (tumor burden < 0.2% of body weight, moderate anorexia, and weight loss). In healthy rats, all drugs induced transient body weight loss, anorexia, and poor N balance. At day 6 posttreatment, all animals had resumed normal feed intake and positive N balance except CDDP-treated rats, which showed continued weight loss and poor N balance. CDDP and MTX exhibited antitumor activity; however, CDDP induced diarrhea in six of eight tumor-bearing rats. Drug-induced anorexia was more severe in tumor-bearing than in healthy treated rats. N balance was more severely decreased in MH7777-bearing rats than in healthy treated animals in response to 5-FU (159 +/- 36 v 273 +/- 27 mg N/2 d) and MTX (-66 +/- 36 v 153 +/- 37 mg N/2 d) at days 3 to 4 postinjection. These results establish the presence of drug-specific effects on host N balance and the existence of a drug-tumor interaction for N metabolism in the tumor-bearing host.

Animals↗

PubMed1995

Supplemental nutrition with ornithine alpha-ketoglutarate in rats with cancer-associated cachexia: surgical treatment of the tumor improves efficacy of nutritional support.

We investigated the use of ornithine alpha-ketoglutarate in treatment of rats bearing Morris hepatoma 7777. Rats received diets containing either ornithine alpha-ketoglutarate, which has been used in other catabolic states (i.e. injury, sepsis), or an isonitrogenous, isocaloric diet containing glycine. Untreated tumors grew to a mass of 11 g/100 g body weight over the 3-wk period after implantation and induced progressive anorexia, negative nitrogen balance, and body and tissue wasting. Compared with glycine, ornithine alpha-ketoglutarate had no effect on tumor growth, but also did not alter the catabolic effects of the tumor on its host. We hypothesized that capture of amino acids by the tumor limited the efficacy of supplemental nutrition here and in published reports in which tumor burden comprised 4-30% of body weight. This is supported by our observation that a 3-wk of implantation the rate of protein deposition plus amino acid oxidation by the tumor was equivalent to approximately 70% of the host's daily protein intake. To parallel the clinical situation in which tumor burden is small at diagnosis and initiation of treatment, the same diets were tested in rats treated by excision of the tumor at a limited stage of the disease. Rats received 3 d preoperative nutrition with ornithine alpha-ketoglutarate or glycine, and continued on the same diets for 3 or 6 d postoperatively. Compared with glycine-fed rats, ornithine alpha-ketoglutarate-fed rats showed a more positive nitrogen balance, higher concentrations of glutamine and branched-chain amino acids in muscle, and accelerated protein deposition in small intestine (P < 0.05). Our results explain the lack of success of nutritional support in untreated cancer and underline the need for clinically relevant animal models for further studies.

Amino Acids↗

PubMed1995

Tissue protein turnover is altered during catch-up growth following Escherichia coli infection in weanling rats.

Infection in young growing animals is manifested by poor tissue protein accretion; during subsequent catch-up growth this is reversed. To account for these changes, protein synthesis and degradation were measured in vivo in skeletal muscle, skin, liver and small intestine in weanling rats during catch-up growth after Escherichia coli infection. Observations were made at d 4, 6, 8, 11 and 14, when infected rats had elevated nitrogen balance. Liver protein mass and turnover were not affected by treatment. Although protein mass of small intestine fell during infection, catch-up was achieved before d 4, suggesting a high priority for protein repletion in this tissue. On d 4, protein mass was lower (P < 0.05) in muscle (-19%) and skin (-23%) in infected vs. control rats. Thereafter growth rates of skeletal muscle and skin were higher (P < 0.001) in infected rats compared with controls. Catch-up growth was most pronounced early, but continued throughout the study. During catch-up growth, protein synthesis (mg/d) in muscle and skin was not different between control and infected animals. Protein synthesis was maintained in muscle because RNA mass was maintained. During catch-up growth in muscle and skin of infected rats, there was lower protein degradation (mg/d) than in controls (P < 0.05). We conclude that alterations in protein turnover during catch-up growth are tissue and time dependent and are different from those described in other hyperanabolic states.

Animals↗

PubMed1995

Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma.

Rats implanted with Yoshida ascites hepatoma (YAH) show a rapid and selective loss of muscle protein due mainly to a marked increase (63-95%) in the rate of protein degradation (compared with rates in muscles of pair-fed controls). To define which proteolytic pathways contribute to this increase, epitrochlearis muscles from YAH-bearing and control rats were incubated under conditions that modify different proteolytic systems. Overall proteolysis in either group of rats was not affected by removal of Ca2+ or by blocking the Ca(2+)-dependent proteolytic system. Inhibition of lysosomal function with methylamine reduced proteolysis (-12%) in muscles from YAH-bearing rats, but not in muscles of pair-fed rats. When ATP production was also inhibited, the remaining accelerated proteolysis in muscles of tumor-bearing rats fell to control levels. Muscles of YAH-bearing rats showed increased levels of ubiquitin-conjugated proteins and a 27-kDa proteasome subunit in Western blot analysis. Levels of mRNA encoding components of proteolytic systems were quantitated using Northern hybridization analysis. Although their total RNA content decreased 20-38%, pale muscles of YAH-bearing rats showed increased levels of ubiquitin mRNA (590-880%) and mRNA for multiple subunits of the proteasome (100-215%). Liver, kidney, heart, and brain showed no weight loss and no change in these mRNA species. Muscles of YAH-bearing rats also showed small increases (30-40%) in mRNA for cathepsins B and D, but not for calpain I or heat shock protein 70. Our findings suggest that accelerated muscle proteolysis and muscle wasting in tumor-bearing rats result primarily from activation of the ATP-dependent pathway involving ubiquitin and the proteasome.

Adenosine Triphosphate↗

PubMed1995

Parallel insulin-like growth factor I and insulin resistance in muscles of rats fed a high fat diet.

The possibility of a similarity between insulin-like growth factor-I (IGF-I) and insulin resistance in epitrochlearis muscles of rats fed a high fat diet [20% (wt/wt) fat] vs. a low fat diet [5% (wt/wt) fat] was investigated. Half-maximally and maximally effective concentrations of IGF-I- and insulin-stimulated 3-O-methyl-glucose transport were 2.32 and 25 nM, respectively, for IGF-I, compared with 0.79 and 20 nM for insulin. The high fat diet reduced both responsiveness and sensitivity of IGF-I-stimulated 3-O-methyl-glucose transport in parallel with the impaired insulin-stimulated 3-O-methyl-glucose transport. IGF-I binding at 2.5 nM to incubated epitrochlearis muscle was also decreased by the high fat diet (P < 0.05). Thus, the high fat diet caused simultaneous IGF-I and insulin resistance in rat skeletal muscle. The IGF-I resistance induced by feeding the high fat diet seems at least partially due to a reduction in IGF-I binding.

3-O-Methylglucose↗

PubMed1994

Dietary omega-3 and polyunsaturated fatty acids modify fatty acyl composition and insulin binding in skeletal-muscle sarcolemma.

Feeding animals with diets high in saturated fat induces insulin resistance, and replacing saturated fat isocalorically with poly-unsaturated fat, especially long-chain omega-3 fatty acids, will prevent the development of insulin resistance in skeletal-muscle tissue. To investigate the mechanism, rats were fed on high-fat (20%, w/w) semipurified diets for 6 weeks. Diets containing ratios of polyunsaturated/saturated (P/S) fatty acid of 0.25 (low-P/S diet) and 1.0 (high-P/S diet) were used to study the effect of the level of saturated fat. To study the effects of omega-3 fatty acids, diets with a low-P/S ratio containing either 0 (low-omega-3 diet) or 3.3% (high-omega-3 diet) long-chain omega-3 fatty acids from fish oil were fed. Plasma membrane from skeletal muscle was purified. The content of fatty acids in sarcolemmal phospholipid was significantly related to the dietary composition. Insulin binding to intact sarcolemmal vesicles prepared from rats fed on diets high in omega-3 fatty acids increased 14-fold compared with animals fed on the low-omega-3 diet (P < 0.0001). Feeding rats on a diet with a high P/S ratio increased sarcolemmal insulin binding by 2.3-fold (P < 0.05). Increased insulin binding was due to increased receptor number at the low-affinity high-capacity binding site. Dietary effects on insulin binding were eliminated when studies were carried out on detergent-solubilized membranes, indicating the importance of the phospholipid fatty acyl composition for insulin binding. The results suggest that dietary omega-3 and polyunsaturated fatty acids increase insulin binding to sarcolemma by changing the fatty acyl composition of phospholipid surrounding the insulin receptor, and this might be the mechanism by which dietary fatty acids modify insulin action.

Animals↗

PubMed1994

Ornithine alpha-ketoglutarate limits muscle protein breakdown without stimulating tumor growth in rats bearing Yoshida ascites hepatoma.

The growth of the Yoshida ascites hepatoma AH130 (YAH) is associated with early wasting, depletion of intracellular amino acid pools, and a pronounced activation of protein degradation in skeletal muscle of the host animal. Ornithine alpha-ketoglutarate (OKG) is used in the treatment of hypercatabolic states, and it has been suggested that it may improve nitrogen balance through repletion of free amino acid pools and suppression of protein catabolism. In cancer, OKG might similarly improve host nutritional status or stimulate tumor growth if its metabolites are limiting for tumor growth. Enteral supplementation with OKG was investigated in Sprague-Dawley rats bearing YAH. Tumor-bearing rats were compared with ad libitum- and pair-fed controls. Rats received OKG (3.4 to 4.0 g/kg body weight/d) or an equal amount of nitrogen as glycine (n = 8 in each group) for 5 days. Tumor implantation decreased cumulative food intake (-40%), host weight (-6%), skeletal muscle weight, and free amino acid levels in muscle and plasma. Muscle protein balance was estimated in vitro; decreased protein synthesis (-30%) and increased proteolysis (+113%) were observed in epitrochlearis muscles (EPI) of YAH-bearing rats compared with control groups. OKG had no effect on the wet weight (10 +/- 1 g) and nitrogen content of the tumor, or on free amino acid levels in the tumor. In tumor-bearing rats, OKG improved muscle protein balance by reducing breakdown by 33% and overall amino acid release of incubated EPI by 46%.

Amino Acids↗

PubMed1994

Insulin-like growth factor-1 and insulin resistance in skeletal muscles of adult and old rats.

A study was designed to compare the effects, in vitro, of insulin-like growth factor-1 (IGF-1) and insulin on rat epitrochlearis muscle metabolism during aging (1, 6-8, or 18-20 months). Our results showed that in young epitrochlearis, IGF-1 was equipotent to insulin in stimulating 2-deoxy-glucose and aminoisobutyric acid transport but more potent in increasing tyrosine incorporation into protein. Both insulin and IGF-1 action on glucose transport was decreased in adult compared with young muscle. Whereas an insulin resistance of amino acid transport and protein synthesis was also recorded in adult rat muscle, the stimulatory effect of IGF-1 on these processes was abolished. Thus the degree of resistance observed varied both with the agonist and with the subsequent metabolic process observed. Whereas modifications of IGF-1 action in mature animals may be correlated in part to the dramatic decrease of IGF-1 receptors (80%), no similar observations were recorded for the insulin receptor. Since muscle IGF-1 receptor gene expression did not decrease in parallel with receptor number, an alteration in IGF-1 receptor messenger RNA (mRNA) translation or receptor degradation may be hypothetized. We concluded that: 1) In contrast to glucose transport, intracellular IGF-1 and insulin postreceptor pathways leading to amino acid uptake and protein metabolism differ. 2) Modification in postbinding events might be involved in decreased insulin- and IGF-1-stimulated muscle metabolism during aging.

Age Factors↗